ACCEL: American College of Cardiology Extended LearningACCEL interviews and topical summaries of cardiology's most interesting research areas

Mar 01, 2016

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Cardio-Oncology Intensive: The Birth of a New Sub-specialty

Not that long ago, a cancer diagnosis often meant a fight for life to the end. Quality of life after the fight was not a big issue because survival seemed more an exception than a rule. That has changed, dramatically, in the last couple decades and the sheer number of cancer survivors has brought greater attention to ensuring that cancer treatment does not cause other harms. In short: the cured cancer patient of today does not want to become the HF patient of tomorrow.

Cancer patients are not just living but living longer, often much longer. As of Jan. 2014, the National Cancer Institute reports that there are 14.5 million cancer survivors in the United States, representing more than 4% of the population.1 An estimated 41% of cancer survivors live 10 years or more and 15% live 20 years or more; currently, 60% of survivors are 65 years of age or older.1

At its 2015 Annual Scientific Sessions, the American College of Cardiology (ACC) took a decidedly different approach to the problem with a half-day Cardio-Oncology Intensive. Traditionally, such sessions at national meetings have been cardiotoxicity-related and embedded in focused clinical pathways, like heart failure and CV imaging. These sessions succeeded in highlighting novel developments within specific areas, but struggled with introducing a broader interdisciplinary dialogue and bringing multiple stakeholders to the stage.

This time around, it was a very different approach, with a focus on highly relevant clinical questions in the CV care of patients with cancer and cancer survivors. All debates and panel discussions included members of both cardiology health teams and oncology health teams, thereby allowing the audience to glean perspectives on patient care from both sides of the aisle.

Bonnie Ky, MD, FACC, the Intensive co-chair said, “We have carefully designed this experience to involve many of the world’s leading experts in cardio-oncology and have specifically incorporated key clinical questions facing us today as we care for this growing population.”

“I believe that some of the biggest challenges lay in our traditional approach to patients as ‘oncology’ or ‘cardiology’ patients,” noted Ana Barac, MD, PhD, FACC, the session co-chair. “The cardiology community has a wealth of clinical documents and guidelines to diagnose, follow, treat, and prevent hypertension, hyperlipidemia, coronary disease, and cardiomyopathies, and oncologists have detailed guidelines in managing diverse forms of cancer, but when it comes to a patient who has cardiovascular disease, or develops one, while being treated for cancer, or as a consequence of cancer treatment, our resources are extremely limited.”

Why is it Important Now?

Pamela S. Douglas, MD, MACC, tried to answer this question. She is the Ursula Geller Professor of Research in Cardiovascular Diseases at Duke University (and a Past-President of the ACC).

She cited four reasons why the time is now.

Because We Share Patients and Disease Risk Factors

Cancer and cardiovascular disease (CVD) happen in the same people, namely an aging population, and both have become chronic diseases. Multisystem disease is increasingly common. And we know there are overlapping risk factors for cancer and CVD: smoking, air pollution, inflammation, obesity, a sedentary lifestyle, poor nutrition/diet, and aging.

Because CV Health Is Essential to Good Cancer Outcomes

At presentation, the clinical approach includes risk factor/comorbidity optimization and treatment selection/modifications. During treatment for cancer, cardiotoxicity must be recognized as an issue and optimal care should ensure access to lifesaving therapies, minimize or eliminate off-target effects, and manage on-target effects. Also, treatment should include prevention, surveillance, and management. After treatment is the time to turn attention to late effects, survivorship, and any concomitant CVD.

Because CVD and Cancer Are Inextricably Linked

Heart failure patients with cancer have a 56% increased death risk. Cancer and cancer treatment provides a multiple hit to an already compromised CV system and, we know, ‘CV reserve’ affects treatment and survivorship.

Because We All Need Experts to Help Us

Dr. Douglas said one key issue is that “we are silo’d in our world views and training.” A survey conducted jointly by the ACC and the American Society of Clinical Oncology showed substantial need for expertise. While survey respondents acknowledged that CV considerations are thought to be ‘Very Important’ in cancer for planning treatment (40%), during treatment (45%), and after successful treatment (37%), the respondents felt a substantial current patient load already, with 85% reporting more than 100 CV consultations per year and 69% reporting more than 100 imaging requests. Yet, they admitted limited understanding of “cardio-oncology” due, at least in part, to few training/educational opportunities.

Session co-chair Dr. Barac added that the challenge lies in creating high-level data and evidence to guide how to approach and treat this complex group of patients, suffering from two of the most common diseases today. “We talk about a comprehensive approach to the patient, not the disease, all the time, but we are at a very early stage of an ideal setting where interdisciplinary teams would work seamlessly in creating evidence and guidance for this approach.”

Dr. Barac also noted, “Professional societies have critical roles in achieving this comprehensive care goal by providing a framework for collaborative activities within and across different disciplines that will lead to advancement of clinical care, guideline development, and dissemination of knowledge through education and training. With this Cardio-Oncology Intensive, the ACC and its cardio-oncology working group can bring key health care providers and partners together for important discussions of current practices, challenges, and future goals.”

Current U.S. and European guidelines give a class I recommendation for the use of beta-blockers in patients with symptomatic HF due to reduced left ventricular ejection fraction (LVEF). This is based on evidence that beta-blockers may alleviate inappropriate sympathetic drive, reduce heart rate, and allow better cardiac filling; plus, randomized trials suggest that beta-blocker therapy reduces mortality and morbidity when used alongside angiotensin-converting enzyme (ACE) inhibitors and aldosterone antagonists. However, the uptake of beta-blockers in HF patients is still suboptimal despite the recommendations and the evidence.

There are many likely reasons for this, including a long entrenched belief that starting beta-blockers in HF may make symptoms worse or that beta-blockers should only be commenced in specialized clinics. There has also been concern that the evidence base is not representative of broader clinical practice and that common patient groups, including those with atrial fibrillation (AF), impaired renal function, or diabetes, may not benefit. Moreover, randomized controlled trials (RCTs) have tended to enroll few women and a preponderance of younger patients.

In an effort to fill in some of these blanks, the Beta-Blockers in Heart Failure Collaborative Group (BB-HF) was formed to obtain and analyze individual patient data from the major RCTs of beta-blockers in HF. Indeed, Kotecha et al. recently reported that in patients with HF and concomitant AF, beta-blockers do not reduce mortality or hospital admissions.1

Age and Gender Effects

It is an approach that is required to gain insights into understudied populations. Individual patient data meta-analysis is considered the ‘gold standard’ of meta-analysis for several reasons2:

Allows for the robust examination of subgroups with enhanced sample size.

Makes possible full time-to-event analyses and the generation of hazard ratios adjusted for individual baseline covariates.

Dipak Kotecha, MB CHB, PhD, and colleagues accessed patient-level data of 13,833 participants from 11 RCTs (Table 1) evaluating beta-blocker therapy in patients with reduced LVEF. Excluded from the primary analysis were patients: whose LVEF was ≥ 45% or the LVEF data were missing; with AF, atrial flutter, or who had paced rhythm; with extremes of age outside the range of 40 to 85 years; and with missing data, such as no data for covariates needed for adjustment using the Cox model. Consequently, individual patient data were available for 13,670 patients for the primary outcome analysis (all-cause mortality) and 13,473 patients for secondary outcomes.

Their analysis confirms that beta-blockers reduce mortality and HF-related hospitalization in patients with reduced ejection fraction in sinus rhythm, irrespective of age or gender (Table 2).

Specifically, the BB-HF data show absolute effect sizes that were similar for men and women and similar across age quartiles with no significant interaction using an adjusted continuous hazard model (patient quartiles: median age of 50, 60, 68, and 75 years).

For men, all-cause mortality was significantly lower with active therapy (p < 0.0001) with a number needed to treat (NNT) of 22 to save one life. For women, the p value was 0.0003 and NNT = 27 versus placebo.

The same was true for HF hospitalization: men,

p < 0.0001 and NNT=19; for women,

p < 0.0001, NNT = 20.

In addition, the tolerability of beta-blockers was similar to placebo. Across all ages, discontinuation due to any adverse event was 15.6% in the placebo group and 14.4% with beta-blockers.

The BB-HF authors said that their results reinforce the use of beta-blockers in all HF patients with reduced ejection fraction in sinus rhythm, and discourage the practice of withholding therapy in women or elderly patients.

In 2014, new guidelines were published for managing patients with valvular heart disease (VHD). Why was it time for new guidelines? Rick Nishimura, MD, MACC, writing committee co-chair, offered several reasons:

The new document has more data on natural history of valve disease.

Since previous versions, better imaging and quantification are possible.

Given better outcomes from interventions and ‘less invasive’ interventions, which contribute to a lower threshold for their use today, treatment can be extended to sicker patients.

As for specifics, one of the most significant additions is the new classification of VHD stages that consider the degree of valve narrowing or leakage, the presence of symptoms, the response of the left and/or right ventricle to the valve lesion, and any change in heart rhythm.

The guideline also provides a proposed risk assessment tool that should be applied to all patients considered for intervention. Acknowledging that current scoring systems are useful but limited, the document’s original assessment combines procedure-specific impediments, major organ system compromise, comorbidities, patient frailty, and the STS predicted risk of mortality model. The risk scores—along with the specific risks and benefits—should be discussed with the patient in a shared decision-making process to determine the best therapy for the individual.

“Due to more knowledge regarding the natural history of untreated patients with severe VHD and better outcomes from surgery, we’ve lowered the threshold for operation to include more patients with asymptomatic severe valve disease,” said Dr. Nishimura. “Now, select patients with severe asymptomatic aortic stenosis and severe asymptomatic mitral regurgitation can be considered for intervention, depending on certain other factors, such as operative mortality and in the case of mitral regurgitation, the ability to achieve a durable valve repair.”

A First for TAVR

The document further addresses, for the first time, the use of TAVR. The introduction of TAVR and other new catheter-based therapies have made VHD management increasingly complex, as they have expanded patient options but increased the difficulty of discerning the risk-benefit ratio. The guidelines thus provide separate recommendations on both the timing and choice of these new interventions.

Using TAVR as an example, outcomes have significantly improved from the initial randomized trials of 2006 and the paradigm and question has changed from whether TAVR is appropriate for the sicker patients to whether TAVR will be the first choice for AS therapy in most patients. Granted, aspects of frailty and futility are yet to be determined, plus there remains a need for improvements relating to prevention of stroke, need for pacemaker, and paravalvular leak that must continue to develop.

As Dr. Nishimura put it at ACC.15, these really are guidelines for the 21st Century.

There is an ‘I’ in This Team

The guidelines support the application of a heart team approach, which is now a central concept in the care of patients with severe AS. However, questions recently have been raised about these teams.

In this case, there really is an ‘I’ in team—specifically, a Class I recommendation—and a ‘C’ in team, too: that is, its Level of Evidence (LOE) in both American and European professional society guidelines. Moreover, a heart team is required in the United States for reimbursement for TAVR, yet it comes with an LOE of C?

Recently in JACC, experts published a review paper, noting: “Although much has been written about the importance of a Heart Team approach (including by some of the current authors), we acknowledge that there is no clear consensus on its definition, desired goals, means of implementation, and, importantly, metrics to assess success and unintended consequences.”2

One of the authors of this review, Michael Mack, MD, FACC, of Baylor Scott & White Health in Dallas, TX, noted at ACC.15 that there are reasons for a heart team: the whole really is greater than the sum of its parts, it provides for immediate shared decision making with a patient-centered approach, there really still is a lot to learn and perplexing clinical decisions to make, and a team approach builds camaraderie and esprit-de-corps.

On the other hand, he said, there are reasons NOT to have a TAVR team: most patient decisions have become straightforward; logistics are still an issue; reimbursement for team services remains an issue; and TAVR procedures are becoming single-operator procedures.

Another recent article asked whether the emphasis on heart teams has “crossed the lines of evidence-based medicine.”3 The authors argue that the need for a new decision-making process in the choice of revascularization strategy should be further explored and supported by scientific evidence.

In the JACC review article, Dr. Mack and colleagues noted that wide-scale implementation of an intervention that may affect patient outcomes, including redesign of health care delivery, must be tested to validate effectiveness. There must be a continued focus on equitable reimbursement for services provided by diverse team members and further communication between centers regarding best practices for heart team implementation; formal quality improvement publications with specific details of delivery innovation also would be welcome.

With common definitions and metrics, the JACC authors noted that it may be possible to show that heart teams both enhance quality and reduce costs. They added that the impetus for investigating the utility of heart team interventions stems from the need to demonstrate value in the changing reimbursement environment, in part by documenting improvement in care delivery and related outcomes in a quality “report card.” Objective demonstrations of this sort, they added, will become increasingly important in discussions of payment for quality initiatives at both local and national levels.

(Editor’s Note: This ACCEL interview is with Robert A. Guyton, MD, FACC, a member of the writing committee that produced the current ACC/AHA valvular disease guidelines and a panelist for a session on the topic at ACC.15.)